Symmetrically Branched Polymers
A new class of polymers called dendritic polymers, including Starburst dendrimers (or Dense Star polymers) and Combburst dendrigrafts (or hyper comb branched polymers), recently was developed and studied for various industrial applications. Those polymers often possess: (a) a well defined core molecule, (b) at least two concentric dendritic layers (generations) with symmetrical (equal length) branches and branch junctures, and (c) exterior surface groups, such as, polyamidoamine (PAMAM)-based branched polymers and dendrimers described in U.S. Pat. Nos. 4,435,548; 4,507,466; 4,568,737; 4,587,329; 5,338,532; 5,527,524; and 5,714,166. Other examples include polyethyleneimine (PEI) dendrimers, such as those disclosed in U.S. Pat. No. 4,631,337; polypropyleneimine (PPI) dendrimers, such as those disclosed in U.S. Pat. Nos. 5,530,092; 5,610,268; and 5,698,662; Frechet-type polyether and polyester dendrimers, core shell tectodendrimers and others, as described, for example, in “Dendritic Molecules”, edited by Newkome et al., VCH Weinheim, 1996; “Dendrimers and Other Dendritic Polymers”, edited by Frechet & Tomalia, John Wiley & Sons, Ltd., 2001; and U.S. Pat. No. 7,754,500.
Combburst dendrigrafts are constructed with a core molecule and concentric layers with symmetrical branches through a stepwise synthetic method. In contrast to dendrimers, Combburst dendrigrafts or polymers are generated with monodisperse linear polymeric building blocks (U.S. Pat. Nos. 5,773,527; 5,631,329 and 5,919,442). Moreover, the branch pattern is different from that of dendrimers. For example, Combburst dendrigrafts form branch junctures along the polymeric backbones (chain branches), while Starburst dendrimers often branch at the termini (terminal branches). Due to the living polymerization techniques used, the molecular weight distributions (Mw/Mn) of those polymers (core and branches) often are narrow. Thus, Combburst dendrigrafts produced through a graft-on-graft process are well defined with Mw/Mn ratios often less than about 1.
SBP's, such as dendrimers, are predominantly produced by repetitive protecting and deprotecting procedures through either a divergent or a convergent synthetic approach. Since dendrimers utilize small molecules as building blocks for the cores and the branches, the molecular weight distribution of the dendrimers often is defined. In the case of lower generations, a single molecular weight dendrimer often is obtained.
In addition to dendrimers and dendrigrafts, other SBP's include symmetrical star shaped or comb shaped polymers, such as, symmetrical star shaped or comb shaped polyethyleneoxide (PEO), polyethyleneglycol (PEG), PEI, PPI, polyoxazoline (POX), polymethyloxazoline (PMOX), polyethyloxazoline (PEOX), polystyrene, polymethylmethacrylate, polydimethylsiloxane or a combination thereof.
Asymmetrically Branched Polymers
Unlike SBP's, asymmetrically branched polymers (ABP), particularly asymmetrically branched dendrimers or regular ABP (reg-ABP), often possess a core, controlled and well defined asymmetrical (unequal length) branches and asymmetrical branch junctures as described in U.S. Pat. Nos. 4,289,872; 4,360,646; and 4,410,688.
On the other hand, a random ABP (ran-ABP) possesses: a) no core, b) functional groups both at the exterior and in the interior, c) random/variable branch lengths and patterns (i.e., termini and chain branches), and d) unevenly distributed interior void spaces.
The synthesis and mechanisms of ran-ABPs, such as, made of PEI, was reported by Jones et al., J. Org. Chem. 9, 125 (1944), Jones et al., J. Org. Chem. 30, 1994 (1965) and Dick et al., J. Macromol. Sci. Chem., A4 (6), 1301-1314, (1970)). Ran-ABP, such as those made of POX, i.e., poly(2-methyloxazoline) and poly(2-ethyloxazoline), were reported by Litt (J. Macromol. Sci. Chem. A9(5), 703-727 (1975)) and Warakomski (J. Polym. Sci. Polym. Chem. 28, 3551 (1990)). The synthesis of ran-ABP's often can involve a one-pot divergent or a one-pot convergent method.
Homopolymers
A homopolymer can relate to a polymer or to a polymer backbone composed of the same repeat unit, that is, the hompolymer is generated from the same monomer (e.g., polyethyleneimine dendrimers, polyamidoamine dendrimers or polyoxazoline dendrimers). The monomer can be a simple compound or a complex or an assemblage of compounds where the assemblage or complex is the repeat unit in the homopolymer. Thus, if an assemblage is composed of three compounds, A, B and C; the complex can be depicted as ABC. A polymer composed of (ABC)-(ABC)-(ABC) . . . is a homopolymer for the purposes of the instant disclosure. The homopolymer may be linear or branched. Thus, in the case of a randomly branched PEI, although there are branches of different length and branches occur randomly, that molecule is a homopolymer for the purposes of the instant disclosure because that branched polymer is composed of a single monomer, ethyleneimine or aziridine. Also, one or more of the monomer or complex monomer components can be modified, substituted, derivatized and so on, for example, modified to carry a functional group. Such molecules are homopolymers for the purposes of the instant disclosure as the backbone is composed of a single simple or complex monomer.
Poorly Water Soluble Drugs
Small molecule drug candidates and drugs, as well as biological molecules, which can be modified for particular purposes or to have particular properties, may be poorly soluble or insoluble in water. Generally, the need for hydrophilicity for a molecule to survive in circulation or in tissue spaces can constrain the use of pharmacologically active hydrophobic drug candidates or drugs. Hence, development of effective formulations for poorly water soluble pharmaceutically active agents (PAA) is important in drug development and use. Current solutions include improving drug solubility or reducing drug particle size by, for example, chemical modification or physical formulation.
Chemical modification methods often involve converting the drug, e.g., by using a salt form, hydrating or attaching various water soluble functional groups, such as, amino/imino, hydroxyl, or carboxyl containing groups; water soluble polymers, such as, PEG or PEO, and the like to the original drug molecule to enhance water solubility.
Physical formulation can include using a cosolvent and/or a surfactant to dissolve a poorly soluble drug; involving a lipid or a liposome-based nanoemulsion or microemulsion; melting drug and polymer without any solvents at elevated temperatures; using a complexing agent (e.g., an inorganic salt, coordination metals (e.g., hexamine cobalt (III) chloride), chelates (e.g., EDTA, EGTA etc.), metal-olefins or metallocenes (e.g., Ferrocene), inclusion compounds (e.g., cyclodextrins, choleic acid etc.) or molecular complexes); as well as solid dispersion in a carrier, such as, e.g., acids, such as, citric acid, tartaric acid, succinic acid, HCl etc.), sugars (e.g., dextrose, sorbitol, sucrose, maltose, galactose, xylitol etc.), polymeric materials (e.g., polyvinylpyrrolidone, PEG-400, PEG-1000, PEG-4000, PEG-6000, carboxymethyl cellulose, hydroxypropyl cellulose, guar gums, xanthan gums, sodium alginates, methyl celluloses, HPMC, cyclodextrins and their derivatives, galactomannans, surfactants (e.g., polyoxyethylene stearate, a poloxamer, a deoxycholic acid, a Tween, a Span, a Gelucire, a vitamin E TPGS etc.), and the like (e.g., pentaerythritol, urea, urethane, hydroxyalkyl xanthenes etc.).
Other known strategies include drug particle size reduction, for example, micronization, which can use a milling technique, such as, use of a jet mill or a rotor stator colloid mill to reduce particle size; increase dissolution rate with increased surface area; nanosuspension, which is a submicron colloidal dispersion of pure particles of drugs, which can be stabilized by surfactants; homogenization, which often involves conventional homogenizers, sonicators and high shear fluid processors; wet milling, where the active drug is fragmented in the presence of surfactant by milling or by spraying drug dissolved in a volatile organic solvent into a heated aqueous solution; using supercritical fluids; polymorph changes; using eutectic mixtures; using self microemulsifying drug delivery systems etc.
However, those treatments may compromise pharmacologic activity.
While drugs often can be delivered through various routes, including oral, intrathecal, rectal, intranasal, subdermal, subdural, intramuscular, transdermal, topical, inhalation, injection and so on, intravenous drug delivery allows rapid and direct equilibration of the drug in the circulation, that can enable effective local concentration. A stable and controlled drug release formulation not only can avoid excessively high serum levels just after dosing but also can allow gradual release of the drug in the intravascular compartment.
Microparticles larger than 7 μm are generally cleared from the circulation by the “blood filtering organs,” such as, the spleen, lungs and liver. Therefore, smaller nanoparticles, e.g., 50-500 nm, often possess longer blood circulation times.
Examples of pharmaceutically active agents (PAA), such as, drugs, include, but are not limited to, chlormethine, chlorambucil, busulfan, thiotepa, cyclophosphamide, estramustine, ifosfamide, meclilorethamine, melphalan, uramustine, lonuistine, streptozotocin, dacarbazine, procarbazine, temozolainide, cisplatin, carboplatin, oxaliplatin, satraplatin, (SP-4-3)-(cis)-aminedichloro-[2-methylpyridine]-platinum (II), methotrexate, permetrexed, raltitrexed, trimetrexate, camptothecin, camptothecin derivatives (such as, irinotecan, topotecan etc.), cladribine, chlorodeoxyadenosine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine, azacitidine, capecitabine, cytarabine, edatrexate, floxuridine, 5-fluorouracil, gemcitabine, troxacitabine, bleomycin, dactinomycin, adriamycin, actinomycin, mithramycin, mitomycin, mitoxantrone, porfiromycin, daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin, idarubicin, valrubicin, phenesterine, tamoxifen, piposulfancamptothesin, L-asparaginase, PEG-L-asparaginase, paclitaxel, docetaxel, taxotere, vinblastine, vincristine, vindesine, vinorelbine, irinotecan, topotecan, amsacrine, etoposide, teniposide, fluoxymesterone, testolactone, bicalutamide, cyproterone, flutamide, nilutamide, aminoglutethimide, anastrozole, exemestane, formestane, letrozole, dexamethasone, prednisone, diethylstilbestrol, fulvestrant, raloxifene, toremifene, buserelin, goserelin, leuprolide, triptorelin, medroxyprogesterone acetate, megestrol acetate, levothyroxine, liothyronine, altretamine, arsenic trioxide, gallium nitrate, hydroxyurea, levamisole, mitotane, octreotide, procarbazine, suramin, thalidomide, methoxsalen, sodium porfimer, bortezomib, erlotinib hydrochloride, gefitinib, imatinib mesylate, semaxanib, adapalene, bexarotene, trans-retinoic acid, 9-cis-retinoic acid and N-(4-hydroxyphenyl) retinamide, alemtuzumab, bevacizumab, cetuximab, ibritumomab tiuxetan, rituximab, trastuzumab, gemtuzumab ozogamicin, tositumomab, interferon-α2a, interferon-α and so on, and derivatives and modifications thereof, so long as the drug, or derivative thereof, is poorly soluble or insoluble in water. Some of the molecules above are modified to be more soluble in water. For the purposes of the instant disclosure, such molecules can be modified or altered to remove such modifications resulting in a pharmaceutically active or biologically active molecule which is less hydrophilic and more hydrophobic, that is, poorly water soluble or water insoluble.
Thus, PAA's that are water insoluble or poorly water soluble, or those which are sensitive to acid environments generally cannot be conventionally administered (e.g., by intravenous injection or oral administration). In some circumstances, parenteral administration of such pharmaceuticals can be achieved by emulsification of oil-solubilized drug with an aqueous liquid (such as normal saline), often in the presence of surfactants or emulsifiers to produce an emulsion for administration.
For example, paclitaxel is a water insoluble drug. Paclitaxel is sold as Taxol® by Bristol-Myers Squibb. Paclitaxel is derived from the Pacific Yew tree, Taxus brevifolia (Wan et al., J. Am. Chem. Soc. 93:2325 (1971). Taxanes, including paclitaxel and docetaxel (also sold as Taxotere®) are used to treat various cancers, including, breast, ovarian and lung cancers, as well as colon, and head and neck cancers, etc.
However, the poor aqueous solubility of paclitaxel has hampered the widespread use thereof. Currently, Taxol® and generics thereof are formulated using a 1:1 solution of ethanol:Cremaphor® (polyethyoxylated castor oil) to solubilize the drug. The presence of Cremaphor® has been linked to severe hypersensitivity reactions and consequently requires medication of patients with corticosteroids (e.g., dexamethasone) and antihistamines.
Alternatively, conjugated paclitaxel, for example, Abraxane®, which is produced by mixing paclitaxel with human serum albumin, has eliminated the need for corticosteroids and antihistamine injections. However, Abraxane® generates undesirable side effects, such as, severe cardiovascular events, including chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, hypertension etc, which prevents patients with high cardiovascular risk from using the drug.
Delivery of Poorly Water Soluble Drugs with Surface Modified Branched Polymers
Although branched polymers, including SBP's and ABP's, have been used for drug delivery, those attempts are primarily focused on the chemical attachment of the drug to the polymer, or physical encapsulation of such drugs in the interior through unimolecular encapsulation (U.S. Pat. Nos. 5,773,527; 5,631,329; 5,919,442; and 6,716,450).
For example, dendrimers and dendrigrafts are believed to physically entrap bioactive molecules using unimolecular encapsulation approaches, as described in U.S. Pat. Nos. 5,338,532; 5,527,524; and 5,714,166 for dense star polymers, and U.S. Pat. No. 5,919,442 for hyper comb branched polymers. Similarly, the unimolecular encapsulation of various drugs using SBP's to form a, “dendrimer box,” was reported in Tomalia et al., Angew. Chem. Int. Ed. Engl., 1990, 29, 138, and in “Dendrimers and Other Dendritic Polymers”, edited by Frechet & Tomalia, John Wiley & Sons, Ltd., 2001, 387-424.
Branched core shell polymers with a hydrophobic core and a hydrophilic shell may be used to entrap a poorly water soluble drug through molecular encapsulation. Randomly branched and hyperbranched core shell structures with a hydrophilic core and a hydrophobic shell have also been used to carry a drug through unimolecular encapsulation and pre-formed nanomicelles (U.S. Pat. No. 6,716,450 and Liu et al., Biomaterials 2010, 10, 1334-1341). However, those unimolecular and pre-formed micelle structures are generated in the absence of a drug.
Block copolymers, such as miktoarm polymers (i.e., Y shape/AB2 type star polymers) and linear (A)-dendritic (B) block copolymers, were observed to form sterocomplexes with paclitaxel (Nederberg et al., Biomacromolecules 2009, 10, 1460-1468 and Luo et al., Bioconjugate Chem. 2010, 21, 1216). Those block copolymers closely resemble traditional lipid or AB-type linear block copolymers, which are well known surfactants used for the generation of micelles.
However, such branched block copolymers are difficult to make and thus, are not suitable for mass production.
There are no descriptions of modifying branched homopolymers, which on exposure to a poorly soluble or water insoluble drug, spontaneously form stable aggregates which are suitable for controlled drug delivery.